The proposal summarized herewith is responsive to PAR-12-138 by (1) Developing and accessing platelet functional responses as a unique human model to be studied within the framework of systems biology, (2) development of novel principles for evaluating the functional interpretation of genetic sequence variation in a robustly phenotyped population, and (3) development of integrated mathematical models incorporating genetic variation/gene expression studies for systematic analysis of a relevant phenotype (platelet function) linked to a complex human phenotype (platelet-associated thrombotic disorders such as cerebo/cardiovascular disease, and. The impact is enhanced by directly comparing and developing these model systems using both normal and diseased platelet populations. Platelets mediate the initial first-step in hemostasis through adhesive and aggregatory events, additionally providing the negatively charged phospholipid surface required for the contact phase and propagation of the coagulation cascade. Platelets are fundamentally important in normal hemostasis and pathological thrombosis (i.e. cerebro- and cardiovascular disease), and continue to be intensely studied in drug development, predicated on the well-documented efficacy of antiplatelet agents in acute and preventative (both primary and secondary prophylaxis) settings. Data using various platelet activation models clearly demonstrate that platelet responses to the majority (if not all) agonists is highly variable within the population, supporting the concept of studying platelet functional responses within a systems biology framework that integrates quantitative trait loci (QTL) and gene networks linked to overall platelet responsiveness. In this application, we propose to close the knowledge gap currently existing between advances in platelet genetics and the genetic basis of platelet function, hypothesizing that platelet functional responses can be developed as powerful models for the development of integrated genetic systems in normal and diseased populations. In specific aim 1, we will develop and phenotypically quantify the impact of genetic sequence variants on platelet functional responses in well-defined normal and thrombocythemic cohorts; and in specific aim 2, we propose to develop integrated mathematical algorithms linking genotypic variants and pathways into predictive models of functional platelet responsiveness in healthy and diseased platelets. This proposal builds on long-standing infrastructure, genetic data bases, and interdisciplinary collaborations focusing on platelet biology, and will lead to novel paradigms linking genetic variability to platelet and clinical phenotypes. PHS 416-9 (Rev. 6/09) Page Continuation Format Page